WO2018193090A2 - Process for preparation of eliglustat hemitartrate and intermediates thereof - Google Patents
Process for preparation of eliglustat hemitartrate and intermediates thereof Download PDFInfo
- Publication number
- WO2018193090A2 WO2018193090A2 PCT/EP2018/060185 EP2018060185W WO2018193090A2 WO 2018193090 A2 WO2018193090 A2 WO 2018193090A2 EP 2018060185 W EP2018060185 W EP 2018060185W WO 2018193090 A2 WO2018193090 A2 WO 2018193090A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- eliglustat
- formula
- hemitartrate
- suitable solvent
- reacting
- Prior art date
Links
- KUBARPMUNHKBIQ-VTHUDJRQSA-N eliglustat tartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.C([C@@H](NC(=O)CCCCCCC)[C@H](O)C=1C=C2OCCOC2=CC=1)N1CCCC1.C([C@@H](NC(=O)CCCCCCC)[C@H](O)C=1C=C2OCCOC2=CC=1)N1CCCC1 KUBARPMUNHKBIQ-VTHUDJRQSA-N 0.000 title claims abstract description 117
- 238000000034 method Methods 0.000 title claims abstract description 65
- 238000002360 preparation method Methods 0.000 title claims abstract description 44
- 239000000543 intermediate Substances 0.000 title abstract description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims description 93
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 90
- FJZZPCZKBUKGGU-AUSIDOKSSA-N eliglustat Chemical compound C([C@@H](NC(=O)CCCCCCC)[C@H](O)C=1C=C2OCCOC2=CC=1)N1CCCC1 FJZZPCZKBUKGGU-AUSIDOKSSA-N 0.000 claims description 81
- 229960002856 eliglustat Drugs 0.000 claims description 73
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 61
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 60
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 57
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 45
- 239000000203 mixture Substances 0.000 claims description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 34
- 150000001875 compounds Chemical class 0.000 claims description 29
- -1 eliglustat di-p-toluoyl-D-tartrate salt Chemical class 0.000 claims description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- LTHCSWBWNVGEFE-UHFFFAOYSA-N octanamide Chemical compound CCCCCCCC(N)=O LTHCSWBWNVGEFE-UHFFFAOYSA-N 0.000 claims description 26
- 239000002253 acid Substances 0.000 claims description 20
- 239000002585 base Substances 0.000 claims description 19
- 238000006243 chemical reaction Methods 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 18
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 18
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 17
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 150000003891 oxalate salts Chemical class 0.000 claims description 16
- FEWJPZIEWOKRBE-LWMBPPNESA-N L-(+)-Tartaric acid Natural products OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 claims description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 14
- 239000001358 L(+)-tartaric acid Substances 0.000 claims description 14
- 235000011002 L(+)-tartaric acid Nutrition 0.000 claims description 14
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 14
- 229930195733 hydrocarbon Natural products 0.000 claims description 14
- 150000002430 hydrocarbons Chemical class 0.000 claims description 14
- 239000008096 xylene Substances 0.000 claims description 14
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 12
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- 150000003892 tartrate salts Chemical class 0.000 claims description 12
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 11
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 11
- 239000013557 residual solvent Substances 0.000 claims description 11
- NTOIKDYVJIWVSU-WOJBJXKFSA-N (2r,3r)-2,3-dihydroxy-2,3-bis(4-methylbenzoyl)butanedioic acid Chemical class C1=CC(C)=CC=C1C(=O)[C@@](O)(C(O)=O)[C@](O)(C(O)=O)C(=O)C1=CC=C(C)C=C1 NTOIKDYVJIWVSU-WOJBJXKFSA-N 0.000 claims description 10
- 239000003638 chemical reducing agent Substances 0.000 claims description 10
- 229960000886 eliglustat tartrate Drugs 0.000 claims description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 9
- 150000001298 alcohols Chemical class 0.000 claims description 9
- 238000011065 in-situ storage Methods 0.000 claims description 9
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 9
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 150000002170 ethers Chemical class 0.000 claims description 8
- 150000008282 halocarbons Chemical class 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- CMIBUZBMZCBCAT-HOTGVXAUSA-N (2s,3s)-2,3-bis[(4-methylbenzoyl)oxy]butanedioic acid Chemical compound C1=CC(C)=CC=C1C(=O)O[C@H](C(O)=O)[C@@H](C(O)=O)OC(=O)C1=CC=C(C)C=C1 CMIBUZBMZCBCAT-HOTGVXAUSA-N 0.000 claims description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 6
- 208000015872 Gaucher disease Diseases 0.000 claims description 6
- 238000010908 decantation Methods 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 238000002955 isolation Methods 0.000 claims description 6
- 150000002576 ketones Chemical class 0.000 claims description 6
- 235000006408 oxalic acid Nutrition 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 235000011181 potassium carbonates Nutrition 0.000 claims description 6
- 239000012279 sodium borohydride Substances 0.000 claims description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 6
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 5
- 229930040373 Paraformaldehyde Natural products 0.000 claims description 5
- 238000002441 X-ray diffraction Methods 0.000 claims description 5
- 238000006345 epimerization reaction Methods 0.000 claims description 5
- 229910052763 palladium Inorganic materials 0.000 claims description 5
- 229920002866 paraformaldehyde Polymers 0.000 claims description 5
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 5
- 238000011282 treatment Methods 0.000 claims description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- HGUFODBRKLSHSI-UHFFFAOYSA-N 2,3,7,8-tetrachloro-dibenzo-p-dioxin Chemical compound O1C2=CC(Cl)=C(Cl)C=C2OC2=C1C=C(Cl)C(Cl)=C2 HGUFODBRKLSHSI-UHFFFAOYSA-N 0.000 claims description 4
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 4
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 4
- OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 claims description 4
- 235000010299 hexamethylene tetramine Nutrition 0.000 claims description 4
- 239000004312 hexamethylene tetramine Substances 0.000 claims description 4
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 claims description 4
- 239000012452 mother liquor Substances 0.000 claims description 4
- 239000007800 oxidant agent Substances 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 239000003880 polar aprotic solvent Substances 0.000 claims description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 235000017550 sodium carbonate Nutrition 0.000 claims description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 4
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 3
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 3
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- 239000012298 atmosphere Substances 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 150000004677 hydrates Chemical class 0.000 claims description 3
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- 238000004064 recycling Methods 0.000 claims description 3
- 239000012453 solvate Substances 0.000 claims description 3
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 claims description 2
- OCQAXYHNMWVLRH-QZTJIDSGSA-N (2r,3r)-2,3-dibenzoyl-2,3-dihydroxybutanedioic acid Chemical compound O=C([C@@](O)(C(=O)O)[C@](O)(C(O)=O)C(=O)C=1C=CC=CC=1)C1=CC=CC=C1 OCQAXYHNMWVLRH-QZTJIDSGSA-N 0.000 claims description 2
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- AOSFMYBATFLTAQ-UHFFFAOYSA-N 1-amino-3-(benzimidazol-1-yl)propan-2-ol Chemical compound C1=CC=C2N(CC(O)CN)C=NC2=C1 AOSFMYBATFLTAQ-UHFFFAOYSA-N 0.000 claims description 2
- DVMNOSBSAVUYEU-WOJBJXKFSA-N C1(=CC(=CC=C1)C(=O)[C@@]([C@@](C(=O)O)(O)C(=O)C=1C=C(C=CC1)C)(O)C(=O)O)C Chemical compound C1(=CC(=CC=C1)C(=O)[C@@]([C@@](C(=O)O)(O)C(=O)C=1C=C(C=CC1)C)(O)C(=O)O)C DVMNOSBSAVUYEU-WOJBJXKFSA-N 0.000 claims description 2
- PQUCIEFHOVEZAU-UHFFFAOYSA-N Diammonium sulfite Chemical compound [NH4+].[NH4+].[O-]S([O-])=O PQUCIEFHOVEZAU-UHFFFAOYSA-N 0.000 claims description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 claims description 2
- 239000007868 Raney catalyst Substances 0.000 claims description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 2
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 2
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical compound [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 claims description 2
- JLCHNBRGUPQWKF-UHFFFAOYSA-J [OH-].[C+4].[OH-].[OH-].[OH-] Chemical compound [OH-].[C+4].[OH-].[OH-].[OH-] JLCHNBRGUPQWKF-UHFFFAOYSA-J 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- ASPXBYAQZVXSNS-UHFFFAOYSA-N azane;sulfurous acid;hydrate Chemical compound N.N.O.OS(O)=O ASPXBYAQZVXSNS-UHFFFAOYSA-N 0.000 claims description 2
- NQZKZGHOYUYCHU-UHFFFAOYSA-N boron;tetraethylazanium Chemical compound [B].CC[N+](CC)(CC)CC NQZKZGHOYUYCHU-UHFFFAOYSA-N 0.000 claims description 2
- FLLNLJJKHKZKMB-UHFFFAOYSA-N boron;tetramethylazanium Chemical compound [B].C[N+](C)(C)C FLLNLJJKHKZKMB-UHFFFAOYSA-N 0.000 claims description 2
- JGDFBJMWFLXCLJ-UHFFFAOYSA-N copper chromite Chemical compound [Cu]=O.[Cu]=O.O=[Cr]O[Cr]=O JGDFBJMWFLXCLJ-UHFFFAOYSA-N 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 239000001630 malic acid Substances 0.000 claims description 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- 229940099690 malic acid Drugs 0.000 claims description 2
- 229960002510 mandelic acid Drugs 0.000 claims description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims description 2
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 claims description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 2
- 229910003446 platinum oxide Inorganic materials 0.000 claims description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 2
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 2
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 2
- 235000010265 sodium sulphite Nutrition 0.000 claims description 2
- 239000012458 free base Substances 0.000 claims 1
- 239000011541 reaction mixture Substances 0.000 description 30
- NSFIAKFOCAEBER-QZTJIDSGSA-N (2s,3s)-2,3-dihydroxy-2,3-bis(4-methylphenyl)butanedioic acid Chemical compound C1=CC(C)=CC=C1[C@@](O)(C(O)=O)[C@](O)(C(O)=O)C1=CC=C(C)C=C1 NSFIAKFOCAEBER-QZTJIDSGSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 20
- 239000000047 product Substances 0.000 description 18
- 239000007787 solid Substances 0.000 description 16
- 239000010410 layer Substances 0.000 description 13
- 239000012044 organic layer Substances 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 239000012258 stirred mixture Substances 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 238000009833 condensation Methods 0.000 description 4
- 230000005494 condensation Effects 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 230000003647 oxidation Effects 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- KMUONIBRACKNSN-UHFFFAOYSA-N potassium dichromate Chemical compound [K+].[K+].[O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O KMUONIBRACKNSN-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000002841 Lewis acid Substances 0.000 description 3
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 150000007517 lewis acids Chemical class 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- REEZZSHJLXOIHL-UHFFFAOYSA-N octanoyl chloride Chemical compound CCCCCCCC(Cl)=O REEZZSHJLXOIHL-UHFFFAOYSA-N 0.000 description 3
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 2
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- BNBQRQQYDMDJAH-UHFFFAOYSA-N benzodioxan Chemical compound C1=CC=C2OCCOC2=C1 BNBQRQQYDMDJAH-UHFFFAOYSA-N 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000013618 particulate matter Substances 0.000 description 2
- JYVLIDXNZAXMDK-UHFFFAOYSA-N pentan-2-ol Chemical compound CCCC(C)O JYVLIDXNZAXMDK-UHFFFAOYSA-N 0.000 description 2
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 description 2
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229960001367 tartaric acid Drugs 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- CMYHFJFAHHKICH-SECBINFHSA-N (5s)-5-phenylmorpholin-2-one Chemical compound C1OC(=O)CN[C@H]1C1=CC=CC=C1 CMYHFJFAHHKICH-SECBINFHSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- SCZNXLWKYFICFV-UHFFFAOYSA-N 1,2,3,4,5,7,8,9-octahydropyrido[1,2-b]diazepine Chemical compound C1CCCNN2CCCC=C21 SCZNXLWKYFICFV-UHFFFAOYSA-N 0.000 description 1
- XQFGVGNRDPFKFJ-UHFFFAOYSA-N 1,2,3,5,6,7-hexahydropyrrolo[1,2-b]pyridazine Chemical compound N1CCC=C2CCCN21 XQFGVGNRDPFKFJ-UHFFFAOYSA-N 0.000 description 1
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- JKERPIAGYYBORB-UHFFFAOYSA-N 1-hydroxypyrrolidine-2,5-dione;octanoic acid Chemical compound ON1C(=O)CCC1=O.CCCCCCCC(O)=O JKERPIAGYYBORB-UHFFFAOYSA-N 0.000 description 1
- QQZOPKMRPOGIEB-UHFFFAOYSA-N 2-Oxohexane Chemical compound CCCCC(C)=O QQZOPKMRPOGIEB-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- 238000006220 Baeyer-Villiger oxidation reaction Methods 0.000 description 1
- GOPHOBGXUPFKKQ-UHFFFAOYSA-N C(C(=O)O)(=O)O.C(CCCCCCC)(=O)N Chemical compound C(C(=O)O)(=O)O.C(CCCCCCC)(=O)N GOPHOBGXUPFKKQ-UHFFFAOYSA-N 0.000 description 1
- NXIVMHFXYUMRRV-UHFFFAOYSA-N CC1=CC=CC=C1.C(C(=O)O)(=O)O Chemical compound CC1=CC=CC=C1.C(C(=O)O)(=O)O NXIVMHFXYUMRRV-UHFFFAOYSA-N 0.000 description 1
- TVERPGNIYXWNSF-UHFFFAOYSA-N CCCCCCCC(NC(CN1CCCC1)C(c1ccc2OCCOc2c1)=O)=O Chemical compound CCCCCCCC(NC(CN1CCCC1)C(c1ccc2OCCOc2c1)=O)=O TVERPGNIYXWNSF-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 1
- 208000037326 Gaucher disease type 1 Diseases 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 238000006809 Jones oxidation reaction Methods 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 150000001204 N-oxides Chemical class 0.000 description 1
- FQHRZRCUAPIMDY-LREBCSMRSA-N O[C@@H](C(=O)O)[C@H](C(=O)O)O.C(CCCCCCC)(=O)N Chemical compound O[C@@H](C(=O)O)[C@H](C(=O)O)O.C(CCCCCCC)(=O)N FQHRZRCUAPIMDY-LREBCSMRSA-N 0.000 description 1
- 238000006036 Oppenauer oxidation reaction Methods 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical class OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 238000006859 Swern oxidation reaction Methods 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 241000289690 Xenarthra Species 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 125000005210 alkyl ammonium group Chemical group 0.000 description 1
- PQLAYKMGZDUDLQ-UHFFFAOYSA-K aluminium bromide Chemical compound Br[Al](Br)Br PQLAYKMGZDUDLQ-UHFFFAOYSA-K 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- JYYOBHFYCIDXHH-UHFFFAOYSA-N carbonic acid;hydrate Chemical compound O.OC(O)=O JYYOBHFYCIDXHH-UHFFFAOYSA-N 0.000 description 1
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 229940023332 cerdelga Drugs 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940117975 chromium trioxide Drugs 0.000 description 1
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 1
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 229960001270 d- tartaric acid Drugs 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- BLEBFDYUDVZRFG-UHFFFAOYSA-N dichloromethane;propan-2-ol Chemical compound ClCCl.CC(C)O BLEBFDYUDVZRFG-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000008241 heterogeneous mixture Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 description 1
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 description 1
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 description 1
- 238000012804 iterative process Methods 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- GEVPUGOOGXGPIO-UHFFFAOYSA-N oxalic acid;dihydrate Chemical compound O.O.OC(=O)C(O)=O GEVPUGOOGXGPIO-UHFFFAOYSA-N 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- 238000011170 pharmaceutical development Methods 0.000 description 1
- UEWYUCGVQMZMGY-UHFFFAOYSA-N phenyl 2-bromoacetate Chemical compound BrCC(=O)OC1=CC=CC=C1 UEWYUCGVQMZMGY-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- SATCULPHIDQDRE-UHFFFAOYSA-N piperonal Chemical compound O=CC1=CC=C2OCOC2=C1 SATCULPHIDQDRE-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 238000001144 powder X-ray diffraction data Methods 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 229940090181 propyl acetate Drugs 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000007790 scraping Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- CRWJEUDFKNYSBX-UHFFFAOYSA-N sodium;hypobromite Chemical compound [Na+].Br[O-] CRWJEUDFKNYSBX-UHFFFAOYSA-N 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
- C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
- C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Definitions
- the present disclosure relates to a novel process for the preparation of eliglustat hemitartrate and intermediates thereof.
- the present disclosure also relates to stable amorphous form of eliglustat hemitartrate, process for its preparation and pharmaceutical composition thereof.
- Eliglustat tartrate is chemically described as N-((lR,2R)-l-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-l-hydroxy-3-(pyrrolidin-l-yl)propan-2-yl) octanamide (2R,3R)-2,3-dihydroxysuccinate and is marketed as Cerdelga® by Genzyme Corp. for the long term treatment of adult patients with Gaucher disease type 1.
- Eliglustat hemitartrate has the structure of formula (I).
- U.S. Patent No. 7,196,205 discloses a process for the preparation of eliglustat as shown in scheme-I.
- phenyl-a- bromoacetate is reacted with S-(+)-phenyl glycinol to provide (5S)-5-phenylmorpholin-2-one, which is condensed with benzodioxolane-6-carboxaldehyde to provide (lR,3S,5S,8aS)-l,3-bis- (2',3'-dihydro-benzo[l,4]dioxin-6'-yl)-5-phenyl-tetrahydro-oxazolo[4,3-c][l,4]oxazin-8-one.
- the resulting cycloadduct compound is reacted with pyrrolidine followed by methanol and aqueous hydrochloric acid solution to provide (2S,3R,l"S)-3-(2',3'-dihydro-benzo[l,4]dioxin-6'-yl)-3- hydroxy-2-(2"-hydroxy-l"-phenyl-ethylamino)-l-pyrrolidin-l-yl-propan-l-one, which is further reduced with lithium aluminum hydride and debenzylated with 20% palladium hydroxide on carbon to yield (lR,2R)-2-amino-l-(2',3'-dihydro-benzo[l,4]dioxin-6'-yl)-3-pyrrolidin-l-yl- propan-l-ol.
- the final step involves condensation of the resulting product with octanoic acid N- hydroxysuccinimide ester to yield eliglust
- CN105646442A discloses reaction of (lR,2R)-2-amino- dihydrobenzo[b][l,4]dioxin-6-yl)-3-(pyrrolidin-l-yl)propan-l-ol with boc anhydride followed by benzyl bromide and then de-protection of the boc group to provide (lR,2R)-l-(benzyloxy)-l- (2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-3-(pyrrolidin-l-yl)propan-2-amine. Condensation of the resulting compound with octanoyl chloride yields benzylated eliglustat which is debenzylated by hydrogenation to provide eliglustat.
- U.S. Patent No. 6,916,802 discloses a process for preparing ceramide-like compounds which involves resolution of isomers by chromatography. However, this process is not suitable for large scale industrial preparations. Therefore, there is a need to develop a simple iterative process for the preparation of eliglustat and its tartrate salt which is economical and applicable on an industrial scale.
- U.S. Patent Application Publication No. 2013/137743 discloses crystalline form A of eliglustat hemitartrate and a process for preparation thereof.
- Amorphous eliglustat hemitartrate is known from WO2016/001885 and IN201621009771, in which the amorphous eliglustat hemitartrate is obtained by spray drying or by dissolving eliglustat hemitartrate in a solvent or a mixture of solvent, followed by evaporation under reduced pressure to obtain solid residue.
- the said process is not suitable for industrial application as the residue obtained has a higher amount of residual solvent.
- the obtained amorphous material is not stable and is hygroscopic in nature, and therefore is not suitable in handling and use for pharmaceutical developments.
- amorphous eliglustat hemitartrate obtained herein is non-hygroscopic, substantially free from residual solvent, industrially scalable for bulk manufacturing and stable towards polymorphic conversion at ambient conditions.
- One or more embodiments provide a simple and commercially advantageous process for the preparation of amorphous eliglustat hemitartrate.
- the present invention provides processes for the preparation of eliglustat or its tartrate salt (I). Also provided are: a stable amorphous form of eliglustat hemitartrate, a process for preparation thereof, a pharmaceutical composition comprising the same, and use of eliglustat hemitartrate for treatment of gaucher disease.
- a process for preparation of eliglustat or its tartrate salt comprises:
- a process for preparation of eliglustat or its tartrate salt comprises: (a) reacting racemic eliglustat of formula II)
- di-p-toluoyl-D-tartaric acid in the presence of a suitable solvent to provide di-p- toluoyl-D-tartrate salt of formula (VIII); optionally purifying the di-p-toluoyl-D-tartrate salt of formula (VIII);
- a process for preparation of racemic eliglustat of formula (VII) comprises:
- a process for recycling racemic eliglustat of formula (VII) or its salt comprises:
- eliglustat or its salt is prepared substantially free of impurity eliglustat N-oxide of formula (X)
- novel intermediates N-(2-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-2-oxoethyl)octan-amide of formula (V); N-(l-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-l-oxo-3-(pyrrolidin-l-yl)propan-2-yl)octanamide of formula (VI); oxalate salt of N-(l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-oxo-3-(pyrrolidin-l- yl)propan-2-yl)octanamide of formula (VI); and di-p-toluoyl-D-tartrate salt of eliglustat of formula (VIII), and their pharmaceutically acceptable solvates and hydrates thereof; processes for their preparation; and
- a process for preparation of stable amorphous eliglustat hemitartrate comprises:
- the stable amorphous form of eliglustat hemitartrate is characterized by X-ray powder diffraction as depicted in Fig. 1 and/or Fig. 2.
- a pharmaceutical composition comprises the stable amorphous form of eliglustat hemitartrate together with one or more pharmaceutically acceptable carriers, excipients or diluents.
- stable amorphous eliglustat hemitartrate is used for treatment of Gaucher disease.
- Fig. 1 The X-ray diffraction pattern of stable amorphous eliglustat hemitartrate obtained after drying at about 50-55° C for about 4-6 hours under reduced pressure.
- Fig. 2 The X-ray diffraction pattern of stable amorphous eliglustat hemitartrate after 1 month storage at ambient temperature.
- Lewis acid is used herein to refer to a substance which can accept an unshared electron pair from another molecule.
- ambient temperature refers to a temperature in the range of about 20° C to about 35° C.
- Suitable solvent means a single or a combination of two or more solvents.
- the term "obtaining" means isolating by way of filtration, filtration under vacuum, centrifugation, decantation and the like.
- the product obtained may be further or additionally dried to achieve the desired moisture values.
- the product may be dried in a tray drier, dried under vacuum and/or in a fluid bed drier.
- heartrate salt covers monotartrate and hemitartrate.
- a process for preparation of eliglustat or its tartrate salt comprises:
- the resolution solvent may be a solvent or solvent mixture in which the racemic eliglustat and chiral acid are soluble, either completely or partially.
- Solvents that may be used for salt formation include, but are not limited to, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol and the like; halogenated hydrocarbons such as dichloromethane, chlorobenzene, chloroform and the like or mixtures thereof.
- Chiral acids can be used for resolution, which facilitates the synthesis of desired enantiomers with absolute configurational assignment.
- Suitable chiral acids include any optically enriched chiral acid capable of forming an isolable salt with racemic eliglustat of formula (VIII).
- Non-limiting examples of chiral acids include one or more of: mandelic acid, malic acid, camphor sulfonic acid, di-p-toluoyl-D-tartaric acid, di-m-toluoyl-D-tartaric acid, and di-benzoyl- D-tartaric acid.
- di-0,0'-aroyl-D- or L-tartaric acid can be used as a chiral acid to resolve racemic eliglustat of formula (VII). More preferably, the chiral acid is di-p-toluoyl-D- tartaric acid.
- Suitable bases include any base, either organic or inorganic, which allow release of the eliglustat free base from its salt form. Bases include, but are not limited to, alkali or alkaline earth metal carbonates such as: sodium carbonate, potassium carbonate; bicarbonate such as sodium bicarbonate, potassium bicarbonate; and hydroxide such as sodium hydroxide, potassium hydroxide; or mixtures thereof.
- a process for preparation of eliglustat or its tartrate salt comprises the steps of:
- di-p-toluoyl-D-tartaric acid in the presence of a suitable solvent to provide di-p- toluoyl-D-tartrate salt of formula (VIII); optionally purifying the di-p-toluoyl-D-tartrate salt of formula (VIII)
- racemic eliglustat of formula (VII) is reacted with di-p-toluoyl-D-tartaric acid in the presence of a suitable solvent to provide di-p-toluoyl-D-tartrate salt of formula (VIII).
- Solvents that may be used for salt formation include, but are not limited to: alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol and the like; and halogenated hydrocarbons such as dichloromethane, chlorobenzene, chloroform and the like; or mixtures thereof.
- Eliglustat di-p-toluoyl-D-tartrate salt of formula (VIII) may be purified from solvents selected from, but not limited to, alcohols such as methanol, ethanol, isopropanol and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; hydrocarbons such as toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane and the like; polar aprotic solvents such as dimethylformamide, acetamide and the like; ethers such as tetrahydrofuran, methyl tert. butyl ether and the like; and water; or mixtures thereof.
- solvents selected from, but not limited to, alcohols such as methanol, ethanol, isopropanol and the like; ketones such as acetone, methyl ethyl ketone, methyl is
- eliglustat di-p-toluoyl-D-tartrate salt of formula (VIII) is reacted with a suitable base in the presence of a solvent to provide eliglustat free base of formula (IX).
- Solvents include, but are not limited to: halogenated hydrocarbons such as dichloromethane, ethylene dichloride, chlorobenzene, chloroform and the like; hydrocarbons such as toluene, xylene and the like; and water; or mixtures thereof.
- Bases include, but are not limited to: alkali or alkaline earth metal carbonate such as sodium carbonate, potassium carbonate; bicarbonate such as sodium bicarbonate, potassium bicarbonate; and hydroxide such as sodium hydroxide, potassium hydroxide; or mixtures thereof.
- the reaction may be carried out with dichloromethane, water and potassium carbonate to provide eliglustat free base of formula (IX).
- Eliglustat free base of formula (IX) may be purified from solvents selected from, but not limited to: hydrocarbons such as toluene, xylene, hexane, heptane, cyclohexane and the like; polar aprotic solvents such as dimethylformamide, acetamide and the like; ethers such as tetrahydrofuran, methyl tert. butyl ether and the like; and water; or mixtures thereof.
- solvents selected from, but not limited to: hydrocarbons such as toluene, xylene, hexane, heptane, cyclohexane and the like; polar aprotic solvents such as dimethylformamide, acetamide and the like; ethers such as tetrahydrofuran, methyl tert. butyl ether and the like; and water; or mixtures thereof.
- eliglustat free base of formula (IX) is reacted with L-(+)-tartaric acid in the presence of a suitable solvent to provide eliglustat tartrate, preferably eliglustat hemitartrate (I).
- Solvents include, but are not limited to: hydrocarbons such as toluene, xylene and the like; alcohols such methanol, ethanol, isopropanol and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; and water; or mixtures thereof.
- the reaction may be carried out with toluene, water and L-(+)-tartaric acid to provide eliglustat hemitartrate (I).
- the reaction may be carried out at a temperature of about 10° C to about 130° C, preferably at about 20° C to about 80° C.
- the reaction of eliglustat free base of formula (IX) with L-(+)-tartaric acid may be carried out for about 15 min. to about 4 hours, preferably for about 30 min. to about 2 hours.
- Eliglustat hemitartrate of formula (I) may be isolated from the reaction mixture by evaporation, filtration, concentration, precipitation, cooling, centrifugation, decantation or any other suitable technique known in the art.
- Eliglustat hemitartrate of formula (I) may be isolated from the reaction mixture using solvent.
- Solvent used for isolation may include, but are not limited to: hydrocarbons such as toluene, xylene, hexane, heptane, cyclohexane and the like; and water; or mixtures thereof.
- a process for preparation of racemic eliglustat of formula (VII) comprises:
- the obtained compound of formula (III) is in situ reacted with an aminating agent and hydrochloric acid to provide 2-amino-l-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)ethan-l-one hydrochloride of formula (IV).
- Aminating agents that may be used include, but are not limited to: hexamine, ammonia and the like.
- Solvents that may be used include, but are not limited to: halogenated hydrocarbons such as dichloromethane, chlorobenzene, chloroform and the like; hydrocarbon such as toluene, xylene and the like; or mixtures thereof.
- Non-limiting examples of the octanoic acid derivatives include: corresponding octanoyl halide, symmetric or mixed carboxylic anhydride, and the corresponding sulfonyloxy or imidazole derivatives.
- the reaction can be carried out using condensing agents such as CDI (carbonyldiimidizole), HOBt (1-hydroxybenzotriazole), HATU ((0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate)), TATU ((0- (7-azabenzotriazole-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate)), EDC (l-ethyl-3-(3- dimethylaminopropyl)carbodiimide), and DCC ( ⁇ , ⁇ '-dicyclohexylcarbodiimide) in
- Solvents that may be used include, but are not limited to: halogenated hydrocarbons such as dichloromethane, chlorobenzene, chloroform and the like; hydrocarbon such as toluene, xylene and the like; and ethers such as tetrahydrofuran (THF) and diethyl ether; or mixtures thereof.
- halogenated hydrocarbons such as dichloromethane, chlorobenzene, chloroform and the like
- hydrocarbon such as toluene, xylene and the like
- ethers such as tetrahydrofuran (THF) and diethyl ether; or mixtures thereof.
- Bases that may be used include, but are not limited to: diisopropylethylamine (DIPEA), triethylamine (TEA), diethylamine (DEA), 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), imidazole, ⁇ , ⁇ -dimethyl aniline, 1,5- diazabicyclo[4.3.0]non-5-ene (DBN), potassium carbonate, sodium carbonate, and the like.
- DIPEA diisopropylethylamine
- TEA triethylamine
- DEA diethylamine
- DBU 1,8- diazabicyclo[5.4.0]undec-7-ene
- imidazole ⁇ , ⁇ -dimethyl aniline, 1,5- diazabicyclo[4.3.0]non-5-ene (DBN)
- DBN diazabicyclo[4.3.0]non-5-ene
- the acetylation of formula (IV) may be performed
- compound of formula (VI) is treated with oxalic acid in the presence of a suitable solvent to provide oxalate salt of formula (VI).
- Solvents that may be used for salt formation include, but are not limited to: alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, or mixtures thereof.
- Solvents that may be used for reduction include, but are not limited to: alcohols such as methanol, ethanol, n- propanol, isopropanol, n-butanol, and t-butanol, or mixtures thereof.
- Reduction can be performed by catalytic hydrogenation or with a hydrogenation reducing agent.
- a catalytic hydrogenation reducing agent may include: noble metal catalyst such as Pd, Pt, Rh and Ru supported on carbon, or using a complex of such metal such as palladium, palladium-carbon, palladium hydroxide-carbon, platinum oxide, copper chromite, palladium acetate, platinum- carbon, palladium-alumina, and Raney nickel.
- a hydrogenation reducing agent may include: sulfite compounds such as sodium bisulfite, sodium sulfite, sodium pyrosulfite, ammonium sulfite, ammonium sulfite monohydrate, or ammonium bisulfite; tetra lower alkyl ammonium borohydrides such as tetra methyl ammonium borohydride, tetra ethyl ammonium borohydride, tetra-n-butyl ammonium borohydride, tetra-n-butyl ammonium cyanoborohydride, sodium cyanoborohydride, lithium cyanoborohydride, sodium borohydride, potassium borohydride, lithium aluminum hydride and diborane.
- sulfite compounds such as sodium bisulfite, sodium sulfite, sodium pyrosulfite, ammonium sulfite, ammonium sulfite monohydrate, or ammonium bisulfite
- eliglustat di-p-toluoyl-D-tartrate salt of formula (VIII) is directly converted to eliglustat hemitartrate of formula (I) without isolating the eliglustat free base of formula (IX).
- eliglustat free base of formula (IX) is not isolated but rather converted in situ to the eliglustat hemitartrate of formula (I).
- Eliglustat di-p-toluoyl-D-tartrate salt of formula (VIII) is reacted with a suitable base in the presence of a solvent to provide eliglustat free base of formula (IX), which was in situ reacted with L-(+)-tartaric acid in the presence of a suitable solvent to provide eliglustat tartrate, preferably eliglustat hemitartrate of formula (I).
- the undesired isomer of eliglustat can be recovered from the mother liquors of the resolution step by oxidation, followed by epimerization and reduction to provide racemic eliglustat, which can be recycled for further resolution.
- a process for recycling racemic eliglustat of formula (VII) or its salt comprises:
- the mother liquor obtained after the isolation of the desired eliglustat di-p-toluoyl-D- tartrate salt of formula (VIII) may be oxidized by oxidizing agent such as potassium dichromate, potassium permanganate, hydrogen peroxide, sodium hypochlorite, sodium hypobromite, chromium trioxide in dilute sulfuric acid, mixture of potassium dichromate and dilute sulfuric acid, Jones oxidation, Swern oxidation, Baeyer-Villiger oxidation, Oppenauer oxidation, and Pinnick oxidation, or mixtures thereof.
- Oxidation may be carried out in the presence of a solvent such as: ketone, ether, and a halogenated hydrocarbon, or mixtures thereof.
- the obtained compound of formula (VI) may be epimerized in the presence or absence of base. Reduction of N-(l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-oxo-3-(pyrrolidin-l-yl)propan-2-yl)octanamide of formula (VI) or its oxalate salt may carried out as described above.
- eliglustat or its salt is prepared having a relatively low content of one or more organic impurities compared to known organic impurities in the art.
- a content of eliglustat N-oxide impurity of formula (X) can be controlled to a minimum level by in situ reacting the eliglustat base of formula (IX) with tartaric acid and thereby obtaining eliglustat hemitartrate salt substantially free from eli lustat N-oxide impurity of formula (X)
- novel intermediates N-(2-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-2-oxoethyl) octanamide of formula (V); N-(l-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-l-oxo-3-(pyrrolidin-l-yl)propan-2-yl)octanamide of formula (VI); oxalate salt of N-(l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-oxo-3-(pyrrolidin-l- yl)propan-2-yl) octanamide of formula (VI); and di-p-toluoyl-D-tartrate salt of eliglustat of formula (VIII), and their pharmaceutically acceptable solvates and hydrates thereof; processes for their preparation;
- amorphous eliglustat hemitartrate is non-hygroscopic and does not convert into crystalline form at ambient temperature. Also, amorphous eliglustat hemitartrate, as described herein, is stable against thermal degradation during drying at elevated temperature.
- the amorphous eliglustat hemitartrate is non-hygroscopic.
- the change in the total weight of amorphous eliglustat hemitartrate was found to be about 0.02 weight percent.
- the amorphous eliglustat hemitartrate may be characterized by such non- hygroscopicity upon exposure to an atmosphere of about 36% humidity for a period of 20 hours. This non-hygroscopic nature of the amorphous eliglustat hemitartrate renders it exceptionally suitable for use in preparing pharmaceutical compositions.
- the stable amorphous eliglustat hemitartrate refers to an amorphous form of eliglustat hemitartrate that remains stable towards conversion to crystalline form at ambient temperature for a period of at least 1 month, showing no change in polymorphic form by X-ray powder diffraction when placed at a temperature of 25 ⁇ 2° C at a relative humidity of 60 +5% for 1 month, or at a temperature of 5 ⁇ 2° C for 1 month.
- the stable amorphous eliglustat hemitartrate is substantially free of residual solvent, wherein the term “substantially free of residual solvent” refers to the stable amorphous form of eliglustat hemitartrate having less than 5000 ppm of residual solvent.
- a process for preparation of stable amorphous eliglustat hemitartrate comprises:
- the starting material to be used for the preparation of stable amorphous eliglustat hemitartrate can be obtained by a method known to a person of ordinary skill in the art including, for example, the method described in WO 2016/001885 and/or US Publication No. 2013/0137743, which are incorporated herein by reference.
- the suspension of eliglustat hemitartarate can be obtained by known methods that include direct use of a reaction mixture containing eliglustat hemitartarate that is obtained in the course of its synthesis, or suspension of eliglustat hemitartarate in suitable solvent or mixture of solvents.
- the suspension of eliglustat hemitartrate may be a clear solution with homogenous mixture or a suspension or slurry with a heterogeneous mixture in suitable solvent.
- suitable solvent may include, but is not limited to,: hydrocarbons such as toluene, xylene, methylene dichloride, ethylene dichloride, chlorobenzene and the like; alcohols such as methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, amyl alcohol, ethylene glycol, glycerol and the like; ketones such as acetone, butanone, 2-pentanone, 3- pentanone, methyl butyl ketone, methyl isobutyl ketone and the like; esters such as methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobuty
- solvent is removed to obtain a residue.
- the suspension of eliglustat hemitartrate in solvent may be distilled until partial removal of solvent by distillation under vacuum.
- Suitable techniques that can be used for the removal of solvent include but not limited to: evaporation, simple evaporation, decantation, and rotational drying, or any other suitable technique known in the art.
- the solvent may be removed, optionally under reduced pressures, at temperature less than about 150° C, less than about 100° C, less than about 75° C, less than about 50° C, or any other suitable temperature.
- eliglustat hemitartrate is suspended in toluene under reflux conditions and the water contained in it is removed by azeotropic distillation.
- the solvents of (b) include but are not limited to a group of solvents in which eliglustat hemitartrate is insoluble or poorly soluble or partially soluble.
- the solvents may include, but are not limited to: ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol and the like; and hydrocarbons such as toluene, xylene, hexane, cyclohexane, heptane and the like; or mixtures thereof.
- Embodiments of the process may further comprise dissolving the obtained eliglustat hemitartrate in solvent and removing the solvent to obtain a residue.
- the residue is treated with suitable solvent to obtain an amorphous form of eliglustat hemitartrate.
- an amorphous form of eliglustat hemitartrate is obtained.
- the isolation may be effected by removing the solvent. Suitable techniques which can be used for the removal of solvent include but are not limited to filtration, decantation or any other suitable technique known in the art.
- suitable techniques which can be used for obtaining an amorphous form of eliglustat hemitartrate include, but not limited to, filtration under vacuum, evaporation, decantation or any other suitable technique known in the art.
- the obtained amorphous eliglustat hemitartrate from (c) may be collected by using techniques such as by scraping or by shaking the container or other techniques specific to the equipment used.
- the isolated solid may be optionally further dried to afford an amorphous form of eliglustat hemitartrate. Drying can be carried out under reduced pressure, vacuum tray drying or air drying. Drying can be carried out for any desired times until the required product quality is achieved.
- the obtained eliglustat hemitartrate may be dried under vacuum at about 50° C to 70° C for 6-12 hours to obtain the amorphous form substantially free from residual solvent.
- the obtained amorphous eliglustat hemitartrate is stable under ordinary stability conditions at least for 1 month and does not change to crystalline form.
- the stable amorphous form of eliglustat hemitartrate is characterized by the X-ray powder diffraction substantially as depicted in Fig. 1 and/or Fig. 2.
- a pharmaceutical composition comprises the stable amorphous form of eliglustat hemitartrate together with one or more pharmaceutically acceptable carriers or excipients.
- compositions containing stable amorphous eliglustat hemitartrate may be prepared by using excipients such as diluents, binders, wetting agents, disintegrating agents, surface active agents and lubricants.
- excipients such as diluents, binders, wetting agents, disintegrating agents, surface active agents and lubricants.
- Various modes of administration of the pharmaceutical compositions of the invention may be selected depending on the therapeutic purpose for example tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories or injection preparations.
- stable amorphous eliglustat hemitartrate is for treatment of Gaucher disease.
- the pharmaceutical compositions containing stable amorphous eliglustat hemitartrate disclosed herein can be used for treatment of Gaucher disease.
- HPLC purity of eliglustat hemitartrate was determined using a symmetry CI 8 (250* 4.6mm, 5 ⁇ ) column with a flow rate of 1.2 ml/min; column oven temperature: 40° C; sample tray temperature: ambient; detector: UV at 275nm; injection volume: 20 ⁇ 1; runtime: 65 min.
- the synthetic reaction scheme for eliglustat hemitartrate is as shown in Scheme-Ill.
- Eliglustate hemitartrate Eliglustat
- the reaction mixture was allowed to warm at 25-35° C and then water (700 ml) and dichloromethane (700 ml) were added to the reaction mixture.
- the pH of the reaction mixture was adjusted to 8.0-10.0 with 20% potassium carbonate solution.
- the reaction mixture was stirred for 30 min. and then the layers were separated.
- the organic layer was washed with water (200 ml), distilled out under vacuum and then azeotroped with methanol (100 ml).
- the obtained crude product (VII) was dissolved in methanol (700 ml), and then a solution of di-p-tolyl-D-tartaric acid (74.5 g) in methanol (300 ml) was added at 50-60° C.
- the reaction mixture was stirred at 50-60° C for 1 h. Then the reaction mixture was cooled at 25-35° C and stirred for 2 h. The solid was filtered and washed with methanol (50 ml X 2). Suck dry and mixed the obtained wet cake with methanol (750 ml). The reaction mixture was heated to reflux for 1 h, then the reaction mixture was cooled at 25-35° C and stirred for 2 h. The solid was filtered and washed with methanol (50 ml X 2). The solid was dried at 25-35° C for 2 h and then at 55-65° C for 8 h to give the title product (43.32 g).
- Cyclohexane (40 ml) was added to the obtained residue and stirred for 30 min. The cyclohexane was distilled out under vacuum and then the residue degassed under vacuum to remove traces of solvent. Cyclohexane (200 ml) was added to the obtained residue and stirred for 1 h at 45-55° C. The reaction mixture was cooled to 25-35° C and stirred for 1 h. The solid was filtered and washed with cyclohexane (20ml X 2). The solid was dried at 25-35° C for 2 h and then at 45-55° C for 4 h to give the title product (19.5 g).
- the organic layer was filtered through a Hyflo bed and washed with toluene.
- a solution of L-(+) tartaric acid (9.4 g) in water (200 ml) was added to the obtained toluene layer at 25-35°C and stirred for 30 min.
- the layers were separated, and the aqueous layer (containing product)was filtered to remove particulate matter and washed with water (50 ml).
- the aqueous layer was distilled out under vacuum below 60° C to provide residue. Water (75 ml) was added to the residue at 35-45°C and stirred to provide a clear solution.
- the obtained solution was dried in a vacuum tray dryer at 35-45°C for 2 h and then at 45-55° C for 12 h.
- the obtained product was further dried in a vacuum tray dryer at 45-55°C until the water content was not more than 1.0 %w/w to give the title product (49.89 g).
- the layers were separated and the organic layer was washed with dilute aqueous ammonia solution (-2% w/v) (50 ml) followed by water (50 ml X 3).
- the organic layer was filtered through a Hyflo bed and washed with toluene (25 ml).
- a solution of L-(+) tartaric acid (2.37 g) in water (50 ml) was added to the obtained toluene layer at 25-35° C and stirred for 30 min.
- the layers were separated, and the aqueous layer (containing product)was filtered to remove particulate matter and washed with water (7 ml).
- the aqueous layer was distilled out under vacuum below 60° C to provide residue.
- Residual solvent content (toluene): 0.01wt%.
- the obtained amorphous eliglustat hemitartrate was kept in an open air having about 36% humidity for 20 h to evaluate any change in the water content and thus its hygroscopicity.
- the change in the total weight of amorphous eliglustat hemitartrate found 0.02%, indicating a low degree of hygroscopicity.
- Residual solvent content (toluene): 0.01wt%.
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Abstract
Process for preparation of eliglustat hemitartrate and intermediates thereof Processes for preparation of eliglustat hemitartrate and intermediates thereof are provided. A stable amorphous form of eliglustat hemitartrate pharmaceutical compositions including the amorphous form of eliglustat hemitartrate, and their uses are also provided.
Description
Process for preparation of eliglustat hemitartrate and intermediates thereof
FIELD
The present disclosure relates to a novel process for the preparation of eliglustat hemitartrate and intermediates thereof. The present disclosure also relates to stable amorphous form of eliglustat hemitartrate, process for its preparation and pharmaceutical composition thereof.
BACKGROUND
Eliglustat tartrate is chemically described as N-((lR,2R)-l-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-l-hydroxy-3-(pyrrolidin-l-yl)propan-2-yl) octanamide (2R,3R)-2,3-dihydroxysuccinate and is marketed as Cerdelga® by Genzyme Corp. for the long term treatment of adult patients with Gaucher disease type 1. Eliglustat hemitartrate has the structure of formula (I).
(I)
U.S. Patent No. 7,196,205 (herein, "the '205 patent") discloses a process for the preparation of eliglustat as shown in scheme-I. In the process of '205 patent, phenyl-a- bromoacetate is reacted with S-(+)-phenyl glycinol to provide (5S)-5-phenylmorpholin-2-one, which is condensed with benzodioxolane-6-carboxaldehyde to provide (lR,3S,5S,8aS)-l,3-bis- (2',3'-dihydro-benzo[l,4]dioxin-6'-yl)-5-phenyl-tetrahydro-oxazolo[4,3-c][l,4]oxazin-8-one. The resulting cycloadduct compound is reacted with pyrrolidine followed by methanol and aqueous hydrochloric acid solution to provide (2S,3R,l"S)-3-(2',3'-dihydro-benzo[l,4]dioxin-6'-yl)-3- hydroxy-2-(2"-hydroxy-l"-phenyl-ethylamino)-l-pyrrolidin-l-yl-propan-l-one, which is further reduced with lithium aluminum hydride and debenzylated with 20% palladium hydroxide on carbon to yield (lR,2R)-2-amino-l-(2',3'-dihydro-benzo[l,4]dioxin-6'-yl)-3-pyrrolidin-l-yl- propan-l-ol. The final step involves condensation of the resulting product with octanoic acid N- hydroxysuccinimide ester to yield eliglustat.
Scheme-I
CN105646442A discloses reaction of (lR,2R)-2-amino- dihydrobenzo[b][l,4]dioxin-6-yl)-3-(pyrrolidin-l-yl)propan-l-ol with boc anhydride followed by benzyl bromide and then de-protection of the boc group to provide (lR,2R)-l-(benzyloxy)-l- (2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-3-(pyrrolidin-l-yl)propan-2-amine. Condensation of the resulting compound with octanoyl chloride yields benzylated eliglustat which is debenzylated by hydrogenation to provide eliglustat.
Scheme-II
U.S. Patent No. 6,916,802 discloses a process for preparing ceramide-like compounds which involves resolution of isomers by chromatography. However, this process is not suitable for large scale industrial preparations.
Therefore, there is a need to develop a simple iterative process for the preparation of eliglustat and its tartrate salt which is economical and applicable on an industrial scale.
U.S. Patent Application Publication No. 2013/137743 discloses crystalline form A of eliglustat hemitartrate and a process for preparation thereof.
Amorphous eliglustat hemitartrate is known from WO2016/001885 and IN201621009771, in which the amorphous eliglustat hemitartrate is obtained by spray drying or by dissolving eliglustat hemitartrate in a solvent or a mixture of solvent, followed by evaporation under reduced pressure to obtain solid residue. The said process is not suitable for industrial application as the residue obtained has a higher amount of residual solvent. Moreover, the obtained amorphous material is not stable and is hygroscopic in nature, and therefore is not suitable in handling and use for pharmaceutical developments.
Therefore, there is a need to provide a process for the preparation of stable amorphous eliglustat hemitartrate which is substantially free from residual solvent, industrially scalable for bulk manufacturing, and stable at least at ordinary storage conditions.
The present inventors have found that the amorphous eliglustat hemitartrate obtained herein is non-hygroscopic, substantially free from residual solvent, industrially scalable for bulk manufacturing and stable towards polymorphic conversion at ambient conditions. One or more embodiments provide a simple and commercially advantageous process for the preparation of amorphous eliglustat hemitartrate.
SUMMARY
The present invention provides processes for the preparation of eliglustat or its tartrate salt (I). Also provided are: a stable amorphous form of eliglustat hemitartrate, a process for preparation thereof, a pharmaceutical composition comprising the same, and use of eliglustat hemitartrate for treatment of gaucher disease.
In one aspect, a process for preparation of eliglustat or its tartrate salt comprises:
(a) reacting racemic eliglustat of formula (VII)
(VII)
with a chiral acid in the presence of a suitable solvent to provide a chiral acid salt; optionally purifying the chiral acid salt;
(b) reacting the chiral acid salt with a suitable base to provide eliglustat free base of formula (IX)
optionally purifying the eliglustat free base in a suitable solvent; and
(c) optionally reacting the eliglustat free base of formula (IX) with L-(+)-tartaric acid in the presence of a suitable solvent to provide eliglustat tartrate, preferably eliglustat hemitartrate (I).
In another aspect, a process for preparation of eliglustat or its tartrate salt comprises: (a) reacting racemic eliglustat of formula II)
with di-p-toluoyl-D-tartaric acid in the presence of a suitable solvent to provide di-p- toluoyl-D-tartrate salt of formula (VIII); optionally purifying the di-p-toluoyl-D-tartrate salt of formula (VIII);
(VTTT)
(b) reacting the eliglustat di-p-toluoyl-D-tartrate salt of formula (VIII) with a suitable base to provide eliglustat free base of formula (IX)
(IX)
optionally purifying the eliglustat of formula (IX) in a suitable solvent; and (c) optionally reacting the eliglustat of formula (IX) with L-(+) -tartaric acid in the presence of a suitable solvent to provide eliglustat tartrate, preferably eliglustat hemitartrate (I).
In yet another aspect, a process for preparation of racemic eliglustat of formula (VII) comprises:
(Π)
with chloroacetyl chloride to provide 2-chloro-l-(2,3-dihydrobenzo[b][l,4]dioxin-6- yl)ethan-l-one of formula (III) which is in situ reacted with an aminating agent and hydrochloric acid to provide a hydrochloride salt of 2-amino-l-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl ethan-l-one of formula (IV)
(b) reacting the compound of formula (IV) with octanoic acid or one or more derivatives thereof in the presence of a suitable solvent to provide N-(2-(2,3- dihydrobenzo[b][l,4]dioxin-6- -2-oxoethyl)octanamide of formula (V)
(V)
(c) reacting the compound of formula (V) with paraformaldehyde and pyrrolidine to provide N-(l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-oxo-3-(pyrrolidin-l-yl)propan-2- yl)octanamide of formula (VI); optionally treating the compound of formula (VI) with oxalic acid in the presence of a suitable sol ent to provide an oxalate salt of formula (VI)
(VI) Oxalate
(d) reacting the compound of formula (VI) or its oxalate salt with a suitable reducing agent to provide racemic eliglustat of formula (VII)
In yet another aspect, eli lustat di-p-toluoyl-D-tartrate salt of formula (VIII)
(Vlll)
is directly converted to eliglustat hemitartrate of formula (I) without isolating the eliglustat free base of formula (IX).
In yet another aspect, a process for recycling racemic eliglustat of formula (VII) or its salt, comprises:
(a) reacting mother liquor obtained after isolation of eliglustat di-p-toluoyl-D-tartrate salt of formula (VIII)
(Vlll)
with an oxidizing agent followed by epimerization to provide a compound of formula (VI), optionally treating the com ound of formula (VI)
(VI)
with oxalic acid in the presence of a suitable solvent to provide an oxalate salt of formula (VI); and
(b) reducing the compound of formula (VI) or its oxalate salt to provide a racemic eliglustat of formula (VII)
(VII)
In yet another aspect, eliglustat or its salt is prepared substantially free of impurity eliglustat N-oxide of formula (X)
(X)
In yet another aspect, provided are novel intermediates: N-(2-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-2-oxoethyl)octan-amide of formula (V); N-(l-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-l-oxo-3-(pyrrolidin-l-yl)propan-2-yl)octanamide of formula (VI); oxalate salt of N-(l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-oxo-3-(pyrrolidin-l- yl)propan-2-yl)octanamide of formula (VI); and di-p-toluoyl-D-tartrate salt of eliglustat of formula (VIII), and their pharmaceutically acceptable solvates and hydrates thereof; processes for their preparation; and their uses for the preparation of eliglustat or tartrate salts thereof.
In yet another aspect, provided is a stable amorphous form of eliglustat hemitartrate of formula (I)
(I)
In yet another aspect, a process for preparation of stable amorphous eliglustat hemitartrate comprises:
(a) suspending eliglustat hemitartrate in a suitable solvent and removing the solvent to obtain a residue;
(b) adding a suitable solvent to the residue; and
(c) obtaining the amorphous form of eliglustat hemitartrate.
In yet another aspect, the stable amorphous form of eliglustat hemitartrate is characterized by X-ray powder diffraction as depicted in Fig. 1 and/or Fig. 2.
In yet another aspect, a pharmaceutical composition comprises the stable amorphous form of eliglustat hemitartrate together with one or more pharmaceutically acceptable carriers, excipients or diluents.
In yet another aspect, stable amorphous eliglustat hemitartrate is used for treatment of Gaucher disease.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1: The X-ray diffraction pattern of stable amorphous eliglustat hemitartrate obtained after drying at about 50-55° C for about 4-6 hours under reduced pressure.
Fig. 2: The X-ray diffraction pattern of stable amorphous eliglustat hemitartrate after 1 month storage at ambient temperature.
DETAILED DESCRIPTION
The term "Lewis acid" is used herein to refer to a substance which can accept an unshared electron pair from another molecule.
The term "about", as used herein, means a variation of up to 10% from such values, or in case of a range of values, means up to a 10% variation from both the lower and upper limits of such ranges.
The term "ambient temperature", as used herein, refers to a temperature in the range of about 20° C to about 35° C.
"Suitable solvent" means a single or a combination of two or more solvents.
As used herein, the term "obtaining" means isolating by way of filtration, filtration under vacuum, centrifugation, decantation and the like. The product obtained may be further or additionally dried to achieve the desired moisture values. For example, the product may be dried in a tray drier, dried under vacuum and/or in a fluid bed drier.
The term "tartrate salt" as used herein covers monotartrate and hemitartrate.
In one aspect, a process for preparation of eliglustat or its tartrate salt, comprises:
(VII)
with a chiral acid in presence of a suitable solvent to provide a chiral acid salt; optionally purifying the chiral acid salt;
(b) reacting the chiral acid salt with a suitable base to provide eliglustat free base of formula (IX)
(IX)
optionally purifying the eliglustat free base in a suitable solvent; and
(c) optionally reacting the eliglustat free base of formula (IX) with L-(+)-tartaric acid in the presence of a suitable solvent to provide eliglustat tartrate, preferably eliglustat hemitartrate (I).
The resolution solvent may be a solvent or solvent mixture in which the racemic eliglustat and chiral acid are soluble, either completely or partially. Solvents that may be used for salt formation include, but are not limited to, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol and the like; halogenated hydrocarbons such as dichloromethane, chlorobenzene, chloroform and the like or mixtures thereof.
Chiral acids can be used for resolution, which facilitates the synthesis of desired enantiomers with absolute configurational assignment. Suitable chiral acids include any optically enriched chiral acid capable of forming an isolable salt with racemic eliglustat of formula (VIII). Non-limiting examples of chiral acids include one or more of: mandelic acid, malic acid, camphor sulfonic acid, di-p-toluoyl-D-tartaric acid, di-m-toluoyl-D-tartaric acid, and di-benzoyl- D-tartaric acid. Preferably, di-0,0'-aroyl-D- or L-tartaric acid can be used as a chiral acid to resolve racemic eliglustat of formula (VII). More preferably, the chiral acid is di-p-toluoyl-D- tartaric acid. Suitable bases include any base, either organic or inorganic, which allow release of the eliglustat free base from its salt form. Bases include, but are not limited to, alkali or alkaline earth metal carbonates such as: sodium carbonate, potassium carbonate; bicarbonate such as
sodium bicarbonate, potassium bicarbonate; and hydroxide such as sodium hydroxide, potassium hydroxide; or mixtures thereof.
In another aspect, a process for preparation of eliglustat or its tartrate salt comprises the steps of:
(a) reacting racemic eliglustat of formula VII)
(VII)
with di-p-toluoyl-D-tartaric acid in the presence of a suitable solvent to provide di-p- toluoyl-D-tartrate salt of formula (VIII); optionally purifying the di-p-toluoyl-D-tartrate salt of formula (VIII)
(VTTT)
(b) reacting the eliglustat di-p-toluoyl-D-tartrate salt of formula (VIII) with a suitable base to provide eliglustat free base of formula (IX)
(IX)
optionally purifying the eliglustat of formula (IX) in a suitable solvent; and
(c) optionally reacting the eliglustat of formula (IX) with L-(+) -tartaric acid in the presence of a suitable solvent to provide eliglustat tartrate, preferably eliglustat hemitartrate (I).
In (a), racemic eliglustat of formula (VII) is reacted with di-p-toluoyl-D-tartaric acid in the presence of a suitable solvent to provide di-p-toluoyl-D-tartrate salt of formula (VIII). Solvents that may be used for salt formation include, but are not limited to: alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol and the like; and halogenated hydrocarbons such as dichloromethane, chlorobenzene, chloroform and the like; or mixtures thereof. Eliglustat di-p-toluoyl-D-tartrate salt of formula (VIII) may be purified from solvents
selected from, but not limited to, alcohols such as methanol, ethanol, isopropanol and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; hydrocarbons such as toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane and the like; polar aprotic solvents such as dimethylformamide, acetamide and the like; ethers such as tetrahydrofuran, methyl tert. butyl ether and the like; and water; or mixtures thereof.
In (b), eliglustat di-p-toluoyl-D-tartrate salt of formula (VIII) is reacted with a suitable base in the presence of a solvent to provide eliglustat free base of formula (IX). Solvents include, but are not limited to: halogenated hydrocarbons such as dichloromethane, ethylene dichloride, chlorobenzene, chloroform and the like; hydrocarbons such as toluene, xylene and the like; and water; or mixtures thereof. Bases include, but are not limited to: alkali or alkaline earth metal carbonate such as sodium carbonate, potassium carbonate; bicarbonate such as sodium bicarbonate, potassium bicarbonate; and hydroxide such as sodium hydroxide, potassium hydroxide; or mixtures thereof. Preferably, the reaction may be carried out with dichloromethane, water and potassium carbonate to provide eliglustat free base of formula (IX). Eliglustat free base of formula (IX) may be purified from solvents selected from, but not limited to: hydrocarbons such as toluene, xylene, hexane, heptane, cyclohexane and the like; polar aprotic solvents such as dimethylformamide, acetamide and the like; ethers such as tetrahydrofuran, methyl tert. butyl ether and the like; and water; or mixtures thereof.
In (c), eliglustat free base of formula (IX) is reacted with L-(+)-tartaric acid in the presence of a suitable solvent to provide eliglustat tartrate, preferably eliglustat hemitartrate (I). Solvents include, but are not limited to: hydrocarbons such as toluene, xylene and the like; alcohols such methanol, ethanol, isopropanol and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; and water; or mixtures thereof. Preferably, the reaction may be carried out with toluene, water and L-(+)-tartaric acid to provide eliglustat hemitartrate (I). The reaction may be carried out at a temperature of about 10° C to about 130° C, preferably at about 20° C to about 80° C. The reaction of eliglustat free base of formula (IX) with L-(+)-tartaric acid may be carried out for about 15 min. to about 4 hours, preferably for about 30 min. to about 2 hours. Eliglustat hemitartrate of formula (I) may be isolated from the reaction mixture by evaporation, filtration, concentration, precipitation, cooling, centrifugation, decantation or any other suitable technique known in the art. Eliglustat hemitartrate of formula (I) may be isolated from the reaction mixture using solvent. Solvent used for isolation may
include, but are not limited to: hydrocarbons such as toluene, xylene, hexane, heptane, cyclohexane and the like; and water; or mixtures thereof.
In yet another aspect, a process for preparation of racemic eliglustat of formula (VII) comprises:
(Π)
with chloroacetyl chloride to provide 2-chloro-l-(2,3-dihydrobenzo[b][l,4]dioxin-6- yl)ethan-l-one of formula (III) which is in situ reacted with an aminating agent and hydrochloric acid to provide a hydrochloride salt of 2-amino-l-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)ethan-l-one of formula (IV)
(IV)
(b) reacting the compound of formula (IV) with octanoic acid or one or more derivatives thereof in the presence of a suitable solvent to provide N-(2-(2,3- dihydrobenzo[b][l,4]dioxin-6- -2-oxoethyl)octanamide of formula (V)
(V)
(c) reacting the compound of formula (V) with paraformaldehyde and pyrrolidine to provide N-(l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-oxo-3-(pyrrolidin-l-yl)propan-2- yl)octanamide of formula VI); optionally treating the compound of formula (VI)
(VI) Oxalate
with oxalic acid in the presence of a suitable solvent to provide an oxalate salt of formula (VI); and
(d) reacting the compound of formula (VI) or its oxalate salt with a suitable reducing agent to provide racemic eliglustat of formula (VII)
(VII)
In (a), there is Friedel-Crafts acylation of 2,3-dihydrobenzo [l,4]dioxine of formula (II) with chloroacetyl chloride using suitable solvent and Lewis acid to provide 2-chloro-l-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)ethan-l-one of formula (III). Lewis acids that may be used for include, but are not limited to: aluminum trichloride (AICI3), aluminum tribromide (AlBr3), boron trifluoride, zinc chloride and the like. The obtained compound of formula (III) is in situ reacted with an aminating agent and hydrochloric acid to provide 2-amino-l-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)ethan-l-one hydrochloride of formula (IV). Aminating agents that may be used include, but are not limited to: hexamine, ammonia and the like. Solvents that may be used include, but are not limited to: halogenated hydrocarbons such as dichloromethane, chlorobenzene, chloroform and the like; hydrocarbon such as toluene, xylene and the like; or mixtures thereof.
In (b), there is condensation of 2-amino-l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)ethan-l- one hydrochloride of formula (IV) with octanoic acid or one or more derivatives thereof in the presence of a suitable solvent to provide N-(2-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-2- oxoethyl)octanamide of formula (V). Non-limiting examples of the octanoic acid derivatives include: corresponding octanoyl halide, symmetric or mixed carboxylic anhydride, and the corresponding sulfonyloxy or imidazole derivatives. The reaction can be carried out using condensing agents such as CDI (carbonyldiimidizole), HOBt (1-hydroxybenzotriazole), HATU ((0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate)), TATU ((0- (7-azabenzotriazole-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate)), EDC (l-ethyl-3-(3- dimethylaminopropyl)carbodiimide), and DCC (Ν,Ν'-dicyclohexylcarbodiimide) in organic solvent, optionally in the presence of a base. Solvents that may be used include, but are not limited to: halogenated hydrocarbons such as dichloromethane, chlorobenzene, chloroform and the like; hydrocarbon such as toluene, xylene and the like; and ethers such as tetrahydrofuran (THF) and diethyl ether; or mixtures thereof. Bases that may be used include, but are not limited to: diisopropylethylamine (DIPEA), triethylamine (TEA), diethylamine (DEA), 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU), imidazole, Ν,Ν-dimethyl aniline, 1,5- diazabicyclo[4.3.0]non-5-ene (DBN), potassium carbonate, sodium carbonate, and the like. The acetylation of formula (IV) may be performed in the presence of a catalyst. Examples of catalysts include, but are not limited to: Ν,Ν-dimethyl aminopyridine (DMAP), N-methyl piperazine (NMP), and the like.
In (c),there is Mannich condensation of N-(2-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-2- oxoethyl)octanamide of formula (V) with paraformaldehyde and pyrrolidine in the presence of a solvent to provide N-(l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-oxo-3-(pyrrolidin-l-yl)propan- 2-yl)octanamide of formula (VI). Solvents that may be used include, but are not limited to: hydrocarbon such as toluene, xylene, or mixtures thereof. Optionally, compound of formula (VI) is treated with oxalic acid in the presence of a suitable solvent to provide oxalate salt of formula (VI). Solvents that may be used for salt formation include, but are not limited to: alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, or mixtures thereof.
In (d),there is reduction of N-(l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-oxo-3- (pyrrolidin-l-yl)propan-2-yl)octanamide of formula (VI) or its oxalate salt with a suitable reducing agent to provide racemic eliglustat of formula (VII). Reduction of the ketone group of compound of formula (VI) or its oxalate salt predominantly provides R isomer. Solvents that may be used for reduction include, but are not limited to: alcohols such as methanol, ethanol, n- propanol, isopropanol, n-butanol, and t-butanol, or mixtures thereof. Reduction can be performed by catalytic hydrogenation or with a hydrogenation reducing agent. Examples of a catalytic hydrogenation reducing agent may include: noble metal catalyst such as Pd, Pt, Rh and Ru supported on carbon, or using a complex of such metal such as palladium, palladium-carbon, palladium hydroxide-carbon, platinum oxide, copper chromite, palladium acetate, platinum- carbon, palladium-alumina, and Raney nickel. These catalytic hydrogenation reducing agents are used singly or in combination of two or more types. Examples of a hydrogenation reducing agent may include: sulfite compounds such as sodium bisulfite, sodium sulfite, sodium pyrosulfite, ammonium sulfite, ammonium sulfite monohydrate, or ammonium bisulfite; tetra lower alkyl ammonium borohydrides such as tetra methyl ammonium borohydride, tetra ethyl ammonium borohydride, tetra-n-butyl ammonium borohydride, tetra-n-butyl ammonium cyanoborohydride, sodium cyanoborohydride, lithium cyanoborohydride, sodium borohydride, potassium borohydride, lithium aluminum hydride and diborane.
In yet another aspect, eliglustat di-p-toluoyl-D-tartrate salt of formula (VIII) is directly converted to eliglustat hemitartrate of formula (I) without isolating the eliglustat free base of formula (IX). In this process, eliglustat free base of formula (IX) is not isolated but rather converted in situ to the eliglustat hemitartrate of formula (I). Eliglustat di-p-toluoyl-D-tartrate salt of formula (VIII) is reacted with a suitable base in the presence of a solvent to provide eliglustat free base of formula (IX), which was in situ reacted with L-(+)-tartaric acid in the presence of a suitable solvent to provide eliglustat tartrate, preferably eliglustat hemitartrate of formula (I). This involves an in situ cost-effective process for the preparation of eliglustat hemitartrate of formula (I).
L(+ Tartaric acid
Eliglustate hemitartrate
In order to minimize material loss, the undesired isomer of eliglustat can be recovered from the mother liquors of the resolution step by oxidation, followed by epimerization and reduction to provide racemic eliglustat, which can be recycled for further resolution.
In yet another aspect, a process for recycling racemic eliglustat of formula (VII) or its salt, comprises:
(a) reacting mother liquor obtained after isolation of eliglustat di-p-toluoyl-D-tartrate salt of formula (VIII)
(Will)
with an oxidizing agent followed by epimerization to provide a compound of formula (VI) , optionally treating the compound of formula (VI)
(VI)
with oxalic acid in the presence of a suitable solvent to provide an oxalate salt of formula (VI); and
(b) reducing the compound of formula (VI) or its oxalate salt to provide racemic eliglustat of formula (VII)
(VII)
The mother liquor obtained after the isolation of the desired eliglustat di-p-toluoyl-D- tartrate salt of formula (VIII) may be oxidized by oxidizing agent such as potassium dichromate, potassium permanganate, hydrogen peroxide, sodium hypochlorite, sodium hypobromite, chromium trioxide in dilute sulfuric acid, mixture of potassium dichromate and dilute sulfuric acid, Jones oxidation, Swern oxidation, Baeyer-Villiger oxidation, Oppenauer oxidation, and Pinnick oxidation, or mixtures thereof. Oxidation may be carried out in the presence of a solvent such as: ketone, ether, and a halogenated hydrocarbon, or mixtures thereof. The obtained compound of formula (VI) may be epimerized in the presence or absence of base. Reduction of N-(l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-oxo-3-(pyrrolidin-l-yl)propan-2-yl)octanamide of formula (VI) or its oxalate salt may carried out as described above.
1 . Oxidation
2. Epimerization
Mother liquer of (VIII)
Di-para toluoyl
D-tartaric acid
Methanol
In yet another aspect, eliglustat or its salt is prepared having a relatively low content of one or more organic impurities compared to known organic impurities in the art. A content of eliglustat N-oxide impurity of formula (X) can be controlled to a minimum level by in situ reacting the eliglustat base of formula (IX) with tartaric acid and thereby obtaining eliglustat hemitartrate salt substantially free from eli lustat N-oxide impurity of formula (X)
(X)
In yet another aspect, provided are novel intermediates: N-(2-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-2-oxoethyl) octanamide of formula (V); N-(l-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-l-oxo-3-(pyrrolidin-l-yl)propan-2-yl)octanamide of formula (VI); oxalate salt of N-(l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-oxo-3-(pyrrolidin-l- yl)propan-2-yl) octanamide of formula (VI); and di-p-toluoyl-D-tartrate salt of eliglustat of formula (VIII), and their pharmaceutically acceptable solvates and hydrates thereof; processes for their preparation; and their uses for the preparation of eliglustat or tartrate salts thereof.
In yet another aspect, provided is a stable amorphous form of eliglustat hemitartrate of formula (I)
(I)
The amorphous eliglustat hemitartrate is non-hygroscopic and does not convert into crystalline form at ambient temperature. Also, amorphous eliglustat hemitartrate, as described herein, is stable against thermal degradation during drying at elevated temperature.
In an embodiment, the amorphous eliglustat hemitartrate is non-hygroscopic. In an embodiment, upon exposure to an atmosphere of about 36% humidity for a period of 20 hours, the change in the total weight of amorphous eliglustat hemitartrate was found to be about 0.02 weight percent. Thus, the amorphous eliglustat hemitartrate may be characterized by such non- hygroscopicity upon exposure to an atmosphere of about 36% humidity for a period of 20 hours.
This non-hygroscopic nature of the amorphous eliglustat hemitartrate renders it exceptionally suitable for use in preparing pharmaceutical compositions.
According to another embodiment, the stable amorphous eliglustat hemitartrate refers to an amorphous form of eliglustat hemitartrate that remains stable towards conversion to crystalline form at ambient temperature for a period of at least 1 month, showing no change in polymorphic form by X-ray powder diffraction when placed at a temperature of 25 ±2° C at a relative humidity of 60 +5% for 1 month, or at a temperature of 5 ±2° C for 1 month.
According to another embodiment, the stable amorphous eliglustat hemitartrate is substantially free of residual solvent, wherein the term "substantially free of residual solvent" refers to the stable amorphous form of eliglustat hemitartrate having less than 5000 ppm of residual solvent.
In yet another aspect, a process for preparation of stable amorphous eliglustat hemitartrate comprises :
(a) providing a suspension of eliglustat hemitartrate in a suitable solvent and removing the solvent to obtain residue;
(b) adding a suitable solvent to the residue; and
(c) obtaining the amorphous form of eliglustat hemitartrate.
The starting material to be used for the preparation of stable amorphous eliglustat hemitartrate can be obtained by a method known to a person of ordinary skill in the art including, for example, the method described in WO 2016/001885 and/or US Publication No. 2013/0137743, which are incorporated herein by reference.
The suspension of eliglustat hemitartarate can be obtained by known methods that include direct use of a reaction mixture containing eliglustat hemitartarate that is obtained in the course of its synthesis, or suspension of eliglustat hemitartarate in suitable solvent or mixture of solvents.
The suspension of eliglustat hemitartrate may be a clear solution with homogenous mixture or a suspension or slurry with a heterogeneous mixture in suitable solvent. Suitable solvent may include, but is not limited to,: hydrocarbons such as toluene, xylene, methylene dichloride, ethylene dichloride, chlorobenzene and the like; alcohols such as methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, amyl alcohol, ethylene glycol, glycerol and the like; ketones such as acetone, butanone, 2-pentanone, 3- pentanone, methyl butyl ketone, methyl isobutyl ketone and the like; esters such as methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate and the like; nitriles such as
acetonitrile and the like; ethers such as diethyl ether, diisopropyl ether, methyl t-butyl ether, dibutyl ether, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol and the like; and polar aprotic solvents such as N,N-dimethylformamide, Ν,Ν-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, sulfolane and the like; or mixtures thereof.
In (a), solvent is removed to obtain a residue. The suspension of eliglustat hemitartrate in solvent may be distilled until partial removal of solvent by distillation under vacuum.
Suitable techniques that can be used for the removal of solvent include but not limited to: evaporation, simple evaporation, decantation, and rotational drying, or any other suitable technique known in the art.
The solvent may be removed, optionally under reduced pressures, at temperature less than about 150° C, less than about 100° C, less than about 75° C, less than about 50° C, or any other suitable temperature.
In an embodiment, eliglustat hemitartrate is suspended in toluene under reflux conditions and the water contained in it is removed by azeotropic distillation.
The solvents of (b) include but are not limited to a group of solvents in which eliglustat hemitartrate is insoluble or poorly soluble or partially soluble. The solvents may include, but are not limited to: ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol and the like; and hydrocarbons such as toluene, xylene, hexane, cyclohexane, heptane and the like; or mixtures thereof.
Embodiments of the process may further comprise dissolving the obtained eliglustat hemitartrate in solvent and removing the solvent to obtain a residue. The residue is treated with suitable solvent to obtain an amorphous form of eliglustat hemitartrate.
In (c), an amorphous form of eliglustat hemitartrate is obtained. The isolation may be effected by removing the solvent. Suitable techniques which can be used for the removal of solvent include but are not limited to filtration, decantation or any other suitable technique known in the art.
In an embodiment, suitable techniques which can be used for obtaining an amorphous form of eliglustat hemitartrate include, but not limited to, filtration under vacuum, evaporation, decantation or any other suitable technique known in the art.
The obtained amorphous eliglustat hemitartrate from (c) may be collected by using techniques such as by scraping or by shaking the container or other techniques specific to the equipment used. The isolated solid may be optionally further dried to afford an amorphous form of eliglustat hemitartrate. Drying can be carried out under reduced pressure, vacuum tray drying
or air drying. Drying can be carried out for any desired times until the required product quality is achieved.
The obtained eliglustat hemitartrate may be dried under vacuum at about 50° C to 70° C for 6-12 hours to obtain the amorphous form substantially free from residual solvent. The obtained amorphous eliglustat hemitartrate is stable under ordinary stability conditions at least for 1 month and does not change to crystalline form.
In yet another aspect, the stable amorphous form of eliglustat hemitartrate is characterized by the X-ray powder diffraction substantially as depicted in Fig. 1 and/or Fig. 2.
In yet another aspect, a pharmaceutical composition comprises the stable amorphous form of eliglustat hemitartrate together with one or more pharmaceutically acceptable carriers or excipients.
Pharmaceutical compositions containing stable amorphous eliglustat hemitartrate may be prepared by using excipients such as diluents, binders, wetting agents, disintegrating agents, surface active agents and lubricants. Various modes of administration of the pharmaceutical compositions of the invention may be selected depending on the therapeutic purpose for example tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories or injection preparations.
In yet another aspect, use of stable amorphous eliglustat hemitartrate is for treatment of Gaucher disease. The pharmaceutical compositions containing stable amorphous eliglustat hemitartrate disclosed herein can be used for treatment of Gaucher disease.
The HPLC purity of eliglustat hemitartrate was determined using a symmetry CI 8 (250* 4.6mm, 5μιη) column with a flow rate of 1.2 ml/min; column oven temperature: 40° C; sample tray temperature: ambient; detector: UV at 275nm; injection volume: 20μ1; runtime: 65 min.
All PXRD data reported herein were obtained using Cu K-a radiation having the wavelength 1.541 A using a PanAlytical, Powder X-ray Diffractometer.
In one embodiment, the synthetic reaction scheme for eliglustat hemitartrate is as shown in Scheme-Ill.
Hexamine O
Dichloromethane •NH2 HC1
Isopropyl alcohol
(Π) (III) 1-Octanoyl chloride
Triethylamine
Toluene
Sodium borohydride
Methanol
Scheme-Ill
In another embodiment, the synthetic reaction scheme for eliglustat hemitartrate is shown in Scheme-IV.
,
(VI) Oxalate Toluene (V)
Sodium borohydride
Methanol
Eliglustate hemitartrate Eliglustat
Scheme-IV
The following examples are given for the purpose of illustrating the present invention and should not be considered as limiting the scope of the invention.
EXAMPLES
Example-1: Preparation of 2-amino-l-(2, 3-dihydrobenzo[b][l,4]dioxin-6-yl)ethan-l-one hydrochloride (IV)
To a stirred solution of anhydrous aluminium chloride (108.0 g) in dichloromethane (2100 ml), a solution of chloroacetyl chloride (83.0 g) in dichloromethane (200 ml) was added under nitrogen atmosphere at 10-20°C and stirred for 15 min. Then a solution of 1,4-benzodioxan (100.0 g) in dichloromethane (200 ml) was added slowly to the reaction mixture at 10-20° C and stirred for 1 h. After completion of reaction, the reaction mixture was quenched into dilute hydrochloric acid solution (1500 ml) at 20-35° C, stirred for 1 h and allowed to settle. Organic layer was separated and washed with water (500 ml). Hexamine (113.0 g) was added to the obtained organic layer
and heated to reflux for 10 h. After completion of reaction, the reaction mixture was cooled to 5- 15° C and stirred for 1 h. The precipitated solid was filtered, washed with cold dichloromethane (100 ml X 2) and the product sucked dry. The obtained wet cake was added in to a stirred solution of isopropyl alcohol (600 ml) and hydrochloric acid (300 ml). The reaction mixture was heated to 40-50° C and stirred for 7 h. After completion of the reaction, the reaction mixture was cooled to 5-15° C and stirred for 120 min. The solid was filtered and washed with cold isopropyl alcohol (100 ml X 2). The product was sucked dry and then dried at 60-70° C to give the title product (172.0 g).
1H NMR (DMSO-d6)5: 4.30-4.32 (2H, m), 4.34-4.37 (2H, m), 4.49 (2H, s), 7.03-7.05 (1H, d), 7.52-7.53 (1H, d), 7.54-7.56 (1H, dd), 8.37 (3H, bs).
Mass: 194.1 [M+H] +
Example 2: Preparation of N-(2-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-2- oxoethyl)octanamide (V)
To a stirred mixture of 2-amino-l-(2,3-dihydrobenzo [b] [l,4]dioxin-6-yl)ethan-l-one hydrochloride (100.0 g), 1-octanoyl chloride (92.5 g) and dichloromethane (1000 ml), a solution of triethylamine (110.0 g) in dichloromethane (500 ml) was added under nitrogen atmosphere at
0- 10° C. The reaction mixture was allowed to warm at 25-30° C and stirred for 2 h. After completion of the reaction, water (1000 ml) was added to the reaction mixture and stirred for 30 min. The layers were separated and the organic layer washed with saturated aqueous sodium bicarbonate solution (500 ml). The organic layer was distilled out under vacuum to get residue. The residue was azeotroped with isopropyl alcohol (100 ml) and then degased for 20 min. To the obtained crude product was added isopropyl alcohol (300 ml) and stirred at 75-85° C for 30 min. The reaction mixture was cooled at 20-30° C and stirred for 1 h. The solid was filtered and washed with isopropyl alcohol (50 ml X 2). The solid was dried at 50-60° C to give the title product (118.0 g).
1H NMR (CDC13)5: 0.86-0.89 (3H, t), 1.26-1.35 (8H, m), 1.61-1.71 (2H, m), 2.27-2.31 (2H, t), 4.28-4.30 (2H, m), 4.32-4.34 (2H, m), 4.67-4.68 (2H, d), 6.54(1H, bs), 6.92-6.94 (1H, d), 7.50 (1H, d), 7.52 (lH, s).
Mass: 320.2 [M+H] +
Example 3: Preparation of N-(l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-oxo-3-(pyrrolidin-
1- yl)propan-2-yl)octanamide oxalate (VI)
To a stirred mixture of paraformaldehyde (12.2 g) and pyrrolidine (29.0 g) in toluene (700 ml), N-(2-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-2-oxoethyl)octanamide (100.0 g) was added under nitrogen atmosphere at 25-30° C and stirred for 10 min. The reaction mixture was heated to 55- 65° C and stirred for 6 h. After completion of the reaction, the reaction mixture was cooled to 25-30° C and washed with water (500 ml). The organic layer was separated, and a solution of oxalic acid dihydrate (39.5 g) in isopropyl alcohol (200 ml) was added to the organic layer. The reaction mixture was stirred at 25-30° C for 1 h and at 0-10° C for 2 h. The solid was filtered and washed with toluene (100 ml X 2). The solid was dried at 25-35°C for 2 h and then at 45-55° C for 8 h to give the title product (113.85 g).
1H NMR (DMSO-d6)5: 0.81-0.84 (3H, t), 1.03-1.22 (8H, m), 1.37-1.41 (2H, m), 1.82-1.86 (6H, m), 2.01-2.13 (2H, m), 3.08-3.37(4H, m), 4.27-4.33 (4H, m), 5.46-5.51 (1H, m), 6.96-6.98(lH, d), 7.43-7.48 (2H, d), 8.58-8.60 (1H, d).
Mass: 403.4 [M+H] +
Example 4: Preparation of N-((lR,2R)-l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-hydroxy- 3-(pyrrolidin-l-yl)propan-2-yl)octanamide di-p-tolyl-D-tartrate (VIII)
To a stirred mixture of N-(l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-oxo-3-(pyrrolidin-l- yl)propan-2-yl) octanamide oxalate (100.0 g) and methanol (700 ml), sodium borohydride (9.6 g) was added in 10 equal lots with 10 minute intervals at -20 to -10° C . The reaction mixture was stirred for 1 h. After completion of the reaction, the reaction mixture was quenched with dilute hydrochloric acid (37 ml) solution in 40 ml water within 30 min. The reaction mixture was allowed to warm at 25-35° C and then water (700 ml) and dichloromethane (700 ml) were added to the reaction mixture. The pH of the reaction mixture was adjusted to 8.0-10.0 with 20% potassium carbonate solution. The reaction mixture was stirred for 30 min. and then the layers were separated. The organic layer was washed with water (200 ml), distilled out under vacuum and then azeotroped with methanol (100 ml). The obtained crude product (VII) was dissolved in methanol (700 ml), and then a solution of di-p-tolyl-D-tartaric acid (74.5 g) in methanol (300 ml) was added at 50-60° C. The reaction mixture was stirred at 50-60° C for 1 h. Then the reaction mixture was cooled at 25-35° C and stirred for 2 h. The solid was filtered and washed with methanol (50 ml X 2). Suck dry and mixed the obtained wet cake with methanol (750 ml). The reaction mixture was heated to reflux for 1 h, then the reaction mixture was cooled at 25-35° C and stirred for 2 h. The solid was filtered and washed with methanol (50 ml X 2). The solid was dried at 25-35° C for 2 h and then at 55-65° C for 8 h to give the title product (43.32 g).
1H NMR (DMSO-d6)5: 0.83-0.87 (3H, t), 0.99-1.02 (2H, m), 1.14-1.29 (8H, m), 1.81 (4H, s), 1.95-2.00 (2H, m), 2.37 (6H, s), 3.02-3.24 (6H, m), 4.18-4.22 (5H, m), 4.64-4.65 (1H, d), 5.64 (2H, s), 6.72 (2H, s), 6.79 (1H, s), 7.30-7.32 (4H, d), 7.66-7.68 (1H, d), and 7.82-7.84(4H, d) Mass: 405.3 [M+H] +
Chiral HPLC: Eliglustat (100%), Other isomers (Not Detected)
Example 5: Preparation of N-((lR,2R)-l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-hydroxy- 3-(pyrrolidin-l-yl)propan-2-yl)octanamide (IX) (Eliglustat base)
To a stirred mixture of N-((lR,2R)-l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-hydroxy-3- (pyrrolidin-l-yl)propan-2-yl)octanamide di-p-tolyl-D-tartrate (40 g) in dichloromethane (200 ml) and water (225 ml), a 20% aqueous solution of potassium carbonate (100 ml) was added at 25- 30° C and stirred for 20 min. The layers were separated and the organic layer was washed with water (200 ml). The organic layer distilled out under vacuum to provide residue. Cyclohexane (40 ml) was added to the obtained residue and stirred for 30 min. The cyclohexane was distilled out under vacuum and then the residue degassed under vacuum to remove traces of solvent. Cyclohexane (200 ml) was added to the obtained residue and stirred for 1 h at 45-55° C. The reaction mixture was cooled to 25-35° C and stirred for 1 h. The solid was filtered and washed with cyclohexane (20ml X 2). The solid was dried at 25-35° C for 2 h and then at 45-55° C for 4 h to give the title product (19.5 g).
Example 6: Preparation of amorphous eliglustat hemitartrate
To a stirred mixture of N-((lR,2R)-l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-hydroxy-3-
(pyrrolidin-l-yl)propan-2-yl)octanamide (100.0 g) and water (350 ml), a solution of L-(+) tartaric acid (18.5 g) in water (50 ml) was added at 25-35° C. The reaction mixture was stirred at 25-35° C for 30 min. and at 40-50° C for 30 min. After completion of the reaction, the reaction mixture was filtered and then distilled out under vacuum to provide residue. The obtained residue was stirred in cyclohexane (500 ml) at 25-35° C for 1 h. The solid was filtered and dried at 25-35°C under vacuum to give the title product.
Example 7: Preparation of amorphous eliglustat hemitartrate
To a stirred mixture of N-((lR,2R)-l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-hydroxy-3- (pyrrolidin-l-yl)propan-2-yl)octanamide di-p-tolyl-D-tartrate (100.0 g) in toluene (500 ml) and water (700 ml), a solution of sodium hydroxide (11.1 g) in water (50 ml) was added at 40-50° C and stirred for 30 min. The layers were separated, and the organic layer was washed with water (200 ml X 2). The organic layer was filtered through a Hyflo bed and washed with toluene. A
solution of L-(+) tartaric acid (9.4 g) in water (200 ml) was added to the obtained toluene layer at 25-35°C and stirred for 30 min. The layers were separated, and the aqueous layer (containing product)was filtered to remove particulate matter and washed with water (50 ml). The aqueous layer was distilled out under vacuum below 60° C to provide residue. Water (75 ml) was added to the residue at 35-45°C and stirred to provide a clear solution. The obtained solution was dried in a vacuum tray dryer at 35-45°C for 2 h and then at 45-55° C for 12 h. The obtained product was further dried in a vacuum tray dryer at 45-55°C until the water content was not more than 1.0 %w/w to give the title product (49.89 g).
1H NMR (DMSO-d6)5: 0.84-0.87 (3H, t), 1.07-1.09 (2H, m), 1.10-1.36 (8H, m), 1.75 (4H, m), 1.98-2.03 (2H, m), 2.50-2.55 (1H, m), 2.75 (4H, m), 2.89-2.94 (1H, m), 3.94 (1H, s), 4.08-4.10 (1H, m), 4.18 (4H, s), 4.66-4.67 (1H, d), 6.72-6.73 (2H, d), 6.78 (1H, s) and 7.46-7.49 (1H, d).
Example 8: Preparation of amorphous eliglustat hemitartrate
To a stirred mixture of N-((lR,2R)-l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-hydroxy-3- (pyrrolidin-l-yl)propan-2-yl)octanamide di-p-tolyl-D-tartrate (25.0 g) in toluene (125 ml) and water (175 ml), aqueous ammonia solution (-20% w/v) was added at 25-35° C to adjust the pH between 9.5 to 11 and stirred for 30 min. The layers were separated and the organic layer was washed with dilute aqueous ammonia solution (-2% w/v) (50 ml) followed by water (50 ml X 3). The organic layer was filtered through a Hyflo bed and washed with toluene (25 ml). A solution of L-(+) tartaric acid (2.37 g) in water (50 ml) was added to the obtained toluene layer at 25-35° C and stirred for 30 min. The layers were separated, and the aqueous layer (containing product)was filtered to remove particulate matter and washed with water (7 ml). The aqueous layer was distilled out under vacuum below 60° C to provide residue. Water (18 ml) was added to the residue and stirred to provide a clear solution. The obtained solution was dried in a vacuum tray dryer at 35-45° C for 2 h and then at 40-50° C for 12 h. The obtained product was further dried in a vacuum tray dryer at 40-50° C until the water content not more than 1% w/w to give the title product (12.42 g).
Example 9: Preparation of stable amorphous form of eliglustat hemitartrate
A mixture of eliglustat hemitartrate (12.0 g) and toluene (120 ml) was heated to reflux at 108- 110° C for 3-5 h. The reaction mixture was then allowed to warm at room temperature, and the toluene was decanted from the reaction mixture to provide a gummy residue. Diisopropyl ether (40ml) was added to the residue and stirred for 30 min. at room temperature. The resulting suspension was filtered under vacuum and washed with diisopropyl ether (10ml). The solid was
dried under vacuum at 50-55° C for 4-6 h to give the title compound. The resulting material was packed under nitrogen atmosphere. The obtained amorphous form of eliglustat hemitartrate was characterized by X-ray diffraction pattern as depicted in Fig. 1.
Residual solvent content (toluene): 0.01wt%. The obtained amorphous eliglustat hemitartrate was kept in an open air having about 36% humidity for 20 h to evaluate any change in the water content and thus its hygroscopicity. The change in the total weight of amorphous eliglustat hemitartrate found 0.02%, indicating a low degree of hygroscopicity.
Example 10: Preparation of stable amorphous form of eliglustat hemitartrate
A mixture of eliglustat hemitartrate (12.0 g) and toluene (120 ml) was heated to reflux at 108- 110° C for 3-5 h. The reaction mixture was then distilled out under vacuum to provide gummy residue. Cyclohexane (60 ml) was added to the residue and stirred for 30 min. at room temperature. The resulting suspension was filtered under vacuum and washed with cyclohexane (12 ml). The solid was dried under vacuum at 50-55° C for 4-6 h to give the title compound. The resulting material was packed under nitrogen atmosphere.
Residual solvent content (toluene): 0.01wt%.
When amorphous eliglustat hemitartrate was placed at a temperature of 25 +2° C at a relative humidity of 60 +5% for 1 month, no change was observed in the XRPD pattern, indicating that the amorphous eliglustat hemitartrate described herein is stable.
Claims
CLAIMS:
1. A process for preparation of eliglustat or its tartrate salt, comprising
(a) reacting racemic eliglustat of formula II)
with a chiral acid in the presence of a suitable solvent to provide a chiral acid salt; optionally purifying the chiral acid salt;
(b) reacting the chiral acid salt with a suitable base to provide eliglustat free base of formula
(IX)
optionally purifying the eliglustat free base in a suitable solvent; and
(c) optionally reacting the eliglustat free base of formula (IX) with L-(+) -tartaric acid in the presence of a suitable solvent to provide eliglustat tartrate.
2. The process as claimed in claim 1, wherein the chiral acid is selected from the group consisting of: mandelic acid, malic acid, camphor sulfonic acid, di-p-toluoyl-D-tartaric acid, di- m-toluoyl-D-tartaric acid, and di-benzoyl-D-tartaric acid.
3. The process as claimed in claim 1, wherein the suitable solvent in (a) is selected from the group consisting of: methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, dichloromethane, chlorobenzene, chloroform, and mixtures thereof.
4. The process as claimed in claim 1, wherein the suitable base in (b) is selected from the group consisting of: sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof.
5. The process as claimed in claim 1, wherein the suitable solvent in (c) is selected from the group consisting of: hydrocarbons, alcohols, ketones, water, and mixtures thereof.
6. The process as claimed in claim 1, wherein the suitable solvent in (c) is selected from the group consisting of: toluene, xylene, methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, water, and mixtures thereof.
7. A process for preparation of eliglustat or its tartrate salt, comprising :
(a) reacting racemic eliglustat of formula (VII)
(VII)
with di-p-toluoyl-D-tartaric acid in the presence of a suitable solvent to provide di-p- toluoyl-D-tartrate salt of formula III)
(Will)
optionally purifying the di-p-toluoyl-D-tartrate salt of formula (VIII);
(b) reacting the eliglustat di-p-toluoyl-D-tartrate salt of formula (VIII) with a suitable base to provide eliglustat free base of formula (IX)
(c) optionally reacting the eliglustat of formula (IX) with L-(+) -tartaric acid in the presence of a suitable solvent to provide eliglustat tartrate.
8. A process for preparation of racemic eliglustat of formula (VII) comprising:
(Π)
with chloroacetyl chloride to provide 2-chloro-l-(2,3-dihydrobenzo[b][l,4]dioxin-6- yl)ethan-l-one of formula (III) which is in situ reacted with an aminating agent and hydrochloric acid to provide a hydrochloride salt of 2-amino-l-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl ethan-l-one of formula (IV)
(b) reacting the compound of formula (IV) with octanoic acid or one or more derivatives thereof in the presence of a suitable solvent to provide N-(2-(2,3- dihydrobenzo[b][l,4]dioxin-6- -2-oxoethyl)octanamide of formula (V)
(V)
(c) reacting the compound of formula (V) with paraformaldehyde and pyrrolidine to provide
N-(l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-oxo-3-(pyrrolidin-l-yl)propan-2- yl)octanamide of formula I)
(VI)
optionally treating the compound of formula (VI) with oxalic acid in the presence of a suitable solvent to provide an oxalate salt of formula (VI); and
(d) reacting the compound of formula (VI) or its oxalate salt with a suitable reducing agent to provide racemic eliglustat of formula (VII)
(VII)
9. The process as claimed in claim 8, wherein the aminating agent is selected from the group consisting of: hexamine, ammonia, and mixtures thereof.
10. The process as claimed in claim 8, wherein the suitable solvent in (b) is selected from the group consisting of: halogenated hydrocarbons, hydrocarbons, ethers, and mixtures thereof.
11. The process as claimed in claim 8, wherein the suitable solvent in (b) is selected from the group consisting of: dichloromethane, chlorobenzene, chloroform, toluene, xylene, tetrahydrofuran, diethyl ether, and mixtures thereof.
12. The process as claimed in claim 8, wherein the suitable reducing agent in (d) is selected from the group consisting of: palladium, palladium-carbon, palladium hydroxide-carbon, platinum oxide, copper chromite, palladium acetate, platinum-carbon, palladium-alumina, Raney nickel, sodium bisulfite, sodium sulfite, sodium pyrosulfite, ammonium sulfite, ammonium sulfite monohydrate, ammonium bisulfite, tetra methyl ammonium borohydride, tetra ethyl ammonium borohydride, tetra-n-butyl ammonium borohydride, tetra-n-butyl ammonium cyanoborohydride, sodium cyanoborohydride, lithium cyanoborohydride, sodium borohydride, potassium borohydride, lithium aluminum hydride, diborane, and mixtures thereof.
13. The process as claimed in claim 8, wherein suitable reducing agent in step (d) is selected from the group consisting of: sodium borohydride, potassium borohydride, and mixtures thereof.
14. A process for preparation of eliglustat or its tartrate salt, comprising :
(a) reacting eliglustat di- -toluoyl-D-tartrate salt of formula (VIII)
(VIII)
with a suitable base to provide eli lustat free base of formula (IX)
(ιχ) ; and
(b) optionally reacting eliglustat of formula (IX) in situ with L-(+) -tartaric acid
presence of a suitable solvent to provide eliglustat tartrate.
A process for recycling racemic eliglustat of formula (VII) or its salt, comprising :
(a) reacting mother liquor obtained after isolation of eliglustat di-p-toluoyl-D-tartrate salt of formula (VIII)
(Vlll)
<VI) ; and
(b) reducing the compound of formula (VI) to provide a racemic eliglustat of formula (VII)
(VII)
(V)
(VIII)
and pharmaceutically acceptable solvates and hydrates thereof. 17. A stable amorphous form of eliglustat hemitartrate of formula (I)
18. The stable amorphous form of eliglustat hemitartrate of claim 17, which remains stable towards conversion to crystalline form at a temperature of 25° C at relative humidity of 60 +5% for a time period of at least 1 month.
19. The stable amorphous form of eliglustat hemitartrate of claim 17, which remains stable towards conversion to crystalline form at a temperature of 5° C for a time period of at least 1 month.
20. The stable amorphous form of eliglustat hemitartrate of claim 17, which is non-hygroscopic.
21. The stable amorphous form of eliglustat hemitartrate of claim 17, wherein the change in total weight of amorphous eliglustat hemitartrate is less than 0.5 weight percent upon exposure to an atmosphere of about 36% humidity for 20 hours. 22. The stable amorphous form of eliglustat hemitartrate as claimed in claim 17, characterized by an X-ray diffraction pattern substantially as depicted in Fig. 1.
23. The stable amorphous form of eliglustat hemitartrate as claimed in claim 17, characterized by an X-ray diffraction pattern substantially as depicted in Fig. 2.
24. The stable amorphous form of eliglustat hemitartrate as claimed in claim 17, which is substantially free of residual solvent.
25. The stable amorphous form of eliglustat hemitartrate as claimed in claim 24, which has residual solvent content of 0.01 weight % or less.
26. The stable amorphous form of eliglustat hemitartrate as claimed in claim 17, which substantially free from eliglustat N-oxide im urity of formula (X)
(X)
A process for preparation of stable amorphous eliglustat hemitartrate comprising:
(a) suspending eliglustat hemitartrate in a suitable solvent and removing the solvent to obtain a residue;
(b) adding a suitable solvent to the residue; and
(c) obtaining the amorphous form of eliglustat hemitartrate.
28. The process of claim 27, wherein the suitable solvent in (a) is selected from the group consisting of: hydrocarbons, alcohols, ketones, esters, nitriles, ethers, polar aprotic solvents, and mixtures thereof.
29. The process of claim 27, wherein the suitable solvent in (a) is selected from the group consisting of: toluene, xylene, methylene dichloride, ethylene dichloride, chlorobenzene, and mixtures thereof.
30. The process of claim 27, wherein the suitable solvent in (b) is selected from the group consisting of: ethers, hydrocarbons, and mixtures thereof.
31. The process of claim 27, wherein the suitable solvent in (b) is selected from the group consisting of: diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran,
1,4-dioxane, 2-methoxyethanol, toluene, xylene, hexane, cyclohexane, heptane, and mixtures thereof.
32. The process of claim 27, wherein the stable amorphous eliglustat hemitartrate shows no change in XRPD pattern when it is placed at a temperature of 25 ±2° C at relative humidity of 60 +5% for 1 month and at a temperature of 5 ±2° C for 1 month.
33. The process of claim 27, wherein the stable amorphous eliglustat hemitartrate is obtained by removal of solvent.
34. The process of claim 33, wherein the solvent may be removed by filtration or decantation..
35. A pharmaceutical composition comprising the stable amorphous form of eliglustat hemitartrate according to claim 17 and one or more pharmaceutically acceptable carriers, excipients or diluents.
36. Use of a stable amorphous form of eliglustat hemitartrate according to claim 17 for treatment of Gaucher disease.
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EP3941917A4 (en) * | 2019-03-22 | 2022-12-21 | Piramal Pharma Limited | An improved process for the preparation of eliglustat and its intermediate |
CN118284600A (en) * | 2021-11-12 | 2024-07-02 | 曙方(上海)医药科技有限公司 | Pharmaceutically acceptable salts of irinotecan and crystalline forms thereof |
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